Topical microbicides represent an important potential strategy for preventing the transmission of human immunodeficiency virus (HIV) and sexually transmitted diseases (STD). It is desirable that a topical microbicide product be effective in preventing HIV and STD infections while not irritating the mucosal surface or adversely affecting normal flora of the vagina or rectum, after single and repeated use. It is essential that the in vivo activity of developing topical microbicide products be evaluated prior to recommendations for widespread intravaginal or rectal use. Because clinical trials are too cumbersome and expensive for screening purposes, animal models need to be used. As the proposed combination topical microbicide formulations evolve, we will assess safety of developing formulations in the rectal and vaginal environments using our established animal models for topical microbicide safety testing. When the lead candidate combination formulation has been selected, based partially on these safety evaluations, it will progress to preliminary clinical studies. These proposed studies play a key role in bridging the gap between laboratory and clinical studies aimed at preventing the spread of HIV/STD.